Acid-group-substituted diphenylazetidinones, process for their preparation, medicaments comprising these compounds, and their use

ABSTRACT

One embodiment of the invention relates to compounds of the formula I: 
                         
in which R1, R2, R3, R4, R5 and R6 have the meanings given in the specification. Other embodiments of the invention relate to physiologically acceptable salts of the compounds of formula I, to processes for their preparation and to medicaments comprising these compounds. The compounds of the invention are suitable for use, for example, as hypolipidemics.

This application is a continuation of U.S. application Ser. No. 10/463,388, filed on Jun. 18, 2003 now U.S. Pat. No. 7,176,193, which claims the benefit of the filing dates of German Patent Application Number 10227508.4, filed on Jun. 19, 2002, and U.S. Provisional Application No. 60/418,678, filed on Oct. 15, 2002. All three applications are hereby incorporated by reference.

One embodiment of the invention relates to acid-group-substituted diphenylazetidinones, their physiologically acceptable salts and derivatives having physiological functions.

Diphenylazetidinones (such as, for example, ezetimibe) and their use for treating hyperlipidemia, arteriosclerosis and hypercholesterolemia have already been described [cf. Drugs of the Future 2000, 25(7):679-685 and U.S. Pat. No. 5,756,470].

One embodiment of the invention provides compounds having a therapeutically utilizable hypolipidemic action. For example, one embodiment of the invention relates to novel compounds which, compared-to the compounds described in the prior art, are absorbed to a very low extent. Very low absorption is to be understood as meaning an intestinal absorption of less than about 10%, for example less than or equal to about 5%.

In one embodiment, absorption of the novel compounds of the invention may be less than that of ezetimibe.

In general, pharmaceutically active compounds that are absorbed to a low extent may have considerably fewer side-effects.

Accordingly, the invention relates to compounds of the formula (I)

wherein

-   -   R1, R2, R3, R4, R5, and R6, independently of one another, are         chosen from:         -   (C₀-C₃₀)-alkylene-(LAG)_(q); or         -   (C₀-C₃₀)-alkylene-(LAG)_(q) wherein at least one carbon atom             of the alkylene radical is replaced by a radical chosen             from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—,             —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl),             —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—;             or         -   H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)-alkyl,             CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂,             (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or             O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted             or at least one hydrogen in the alkyl radical is replaced by             fluorine;         -   C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl,             SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl,             SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or             SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl             radical is unsubstituted or substituted one or two times,             each substituent chosen independently from: F, Cl, Br, OH,             CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂;             or         -   NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH(C₁-C₇)-acyl,             phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein             the phenyl ring is unsubstituted or substituted one, two, or             three times, each substituent chosen independently from: F,             Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl,             (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,             SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂;         -   wherein (LAG) is —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂,             —(CH₂)₀₋₁₀—O—P(O)(OH)₂, or —(CH₂)₀₋₁₀—COOH and wherein q is             1-5; and     -   wherein at least one of the radicals R1 to R6 must have the         meaning (C₀-C₃₀)-alkylene-(LAG)_(q); or     -   (C₀-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbon atom of         the alkylene radical is replaced by a radical chosen from:         —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—,         —C≡—C—, —N((C₁-C₆)-alkyl)-, —N(phenyl)-,         —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—,

or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio;

with the proviso that the compound is not 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid, or a compound wherein the radicals R1-R6 have the meaning —O—(CH₂)₁₋₁₀—COOH, (C₁-C₆)-alkylene-COOH or —COOH.

In one embodiment of the invention, at least one of the radicals R1 to R6 in the compounds of the formula I has the meaning: (C₀-C₃₀)-alkylene-(LAG)_(q); or (C₀-C₃₀)-alkylene-(LAG)_(q), wherein at least one carbon atom of the alkylene radical is replaced by —O—, —(C═O)—, —N((C₁-C₆)-alkyl), —N(CO—(CH₂)₁₋₁₀—COOH)— or —NH—.

In another embodiment of the invention, one of the radicals R1 or R3 in the compounds of the formula I has the meaning (C₀-C₃₀)-alkylene-(LAG); or (C₀-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of the alkylene radical is replaced by —O—, —(C═O)—, —N(CH₃)—, or —NH—.

In another embodiment of the invention, one of the radicals R1 or R3 in the compounds of the formula I has the meaning —(CH₂)₀₋₁—Y—W—(C₀-C₂₅)-alkylene-Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C₀-C₂₅)-alkylene-Y′—W′-(LAG), wherein at least one carbon atom of the alkylene radical is replaced by an oxygen atom and wherein Y and W independently of one another are chosen from: NH, NCH₃, C═O, O, a bond, and S(O)_(m), (wherein m=0-2), and wherein Y′ and W′ independently of one another are chosen from: NH, NCH₃, C═O, O, a bond, and S(O)_(m), wherein m=0-2, or Y—W or Y′—W′ in each case, together represent a bond.

In another embodiment of the invention, the group LAG in any of the radicals R1 to R6 in the compounds of the formula I is a carboxylic acid radical or a sulfonic acid radical.

Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the desired properties sought to be obtained by the present invention. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

Owing to their increased solubility in water, pharmaceutically acceptable salts are often more suitable for medical applications than the parent compounds. These salts generally have a pharmaceutically acceptable anion or cation. Examples of suitable pharmaceutically acceptable acid addition salts of the compounds according to the invention include salts of inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, sulfonic acid and sulfuric acid; and of organic acids, such as acetic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid, isothionic acid, lactic acid, lactobionic acid, maleic acid, malic acid, methanesulfonic acid, succinic acid, p-toluenesulfonic acid, tartaric acid and-trifluoroacetic acid. An example of an acceptable salt of the compounds of the invention is the chloride salt. Examples of suitable pharmaceutically acceptable basic salts include ammonium salts, alkali metal salts (such as sodium and potassium salts) and alkaline earth metal salts (such as magnesium and calcium salts).

The scope of the invention also includes salts having a pharmaceutically unacceptable anion, which salts may be useful intermediates for preparing or purifying pharmaceutically acceptable salts and/or for use in nontherapeutic, for example in vitro, applications.

Here, the term “derivative having physiological function” refers to any physiologically acceptable derivative of a compound according to the invention, for example an ester, that is able, upon administration to a mammal, for example a human, to form such a compound or an active metabolite (directly or indirectly).

A further aspect of this invention includes prodrugs of the compounds according to the invention. Such prodrugs can be metabolized in vivo to give a compound according to the invention. These prodrugs may or may not be active in their own right.

The compounds according to the invention can also be present in various polymorphic forms, for example as amorphous and crystalline polymorphous forms.

Accordingly, another aspect of the invention includes the polymorphic forms of the compounds according to the invention.

Hereinbelow, all references to “compound(s) of the formula (I)” refer to a compound or compounds of the formula (I) as described above, and to their salts, solvates and derivatives having physiological function, as described herein.

The compounds of the formula I and their pharmaceutically acceptable salts and derivatives having physiological function are useful medicaments for treating an impaired lipid metabolism, for example hyperlipidemia. The compounds of the formula I are also suitable for modulating the serum cholesterol concentration and for preventing and treating arteriosclerotic manifestations.

As used herein, treating or treatment includes the treating of, for example, a patient inflicted with a disease or condition, as well as the prevention, prophylaxis, or protective treatment of a patient. Treatment also includes treating a subject susceptible to or predisposed to developing a disease or condition, which could include patients in whom the disease or condition has not yet presented, as well as patients in whom the disease has been successfully treated but could redevelop or reoccur.

The compound(s) of the formula (I) can also be administered in combination with other active compounds.

The amount of a compound of the formula (I) required to achieve the desired biological effect depends on a number of factors, for example on the specific compound chosen, on the intended use, on the mode of administration and on the clinical condition of the patient. In general, the daily dose is in the range from 0.1 mg to 100 mg (typically from 0.1 mg to 50 mg) per day per kilogram of bodyweight, for example 0.1-10 mg/kg/day. Tablets or capsules may contain, for example, from 0.01 to 100 mg, typically from 0.02 to 50 mg. In the case of pharmaceutically acceptable salts, the abovementioned weight data relate to the weight of the diphenylazetidinone-ion derived from the salt. An effective amount of a compound of the invention is an amount sufficient to bring about a desired effect. For example, in the context of treating an impaired lipid metabolism, for instance hyperlipidemia, an effective amount of a compound of the invention would constitute an amount sufficient to bring about a beneficial change in the condition of the patient. For the prophylaxis or therapy of the abovementioned conditions, the compounds of the formula (I) can be used by themselves, but they may also be present in the form of a pharmaceutical composition with an acceptable carrier. The carrier must of course be acceptable in the sense that it is compatible with the other constituents of the composition and relatively speaking is not harmful to the health of the patient. The carrier can be a solid or a liquid or both and may be formulated with the compound as an individual dose, for example as a tablet, which can contain from 0.05% to 95% by weight of the active compound. Further pharmaceutically active substances can also be present, including further compounds of the formula (I). The pharmaceutical compositions according to the invention can be prepared by one of the known pharmaceutical methods, which essentially consist in mixing the constituents with pharmacologically acceptable carriers and/or auxiliaries.

Pharmaceutical compositions according to the invention include those which are suitable for oral or peroral (e.g. sublingual) administration, although the most suitable manner of administration is dependent in each individual case on the nature and severity of the condition to be treated and on the type of the compound of the formula (I) used in each case. Coated formulations and coated delayed-release formulations are also included in the scope of the-invention, as are acid-resistant and enteric formulations. Examples of suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.

Suitable pharmaceutical compounds for oral administration can be present in separate units, such as,.for example, capsules, cachets, lozenges or tablets, which in each case contain a specific amount of the compound of the formula (I); as a powder or granules; as a solution or suspension in an aqueous or nonaqueous liquid; or as an oil-in-water or water-in-oil emulsion. As already mentioned, these compositions can be prepared according to any suitable pharmaceutical method that includes a step in which the active compound and the carrier (which can consist of one or more additional constituents) are brought into contact. In general, the compositions are prepared by uniform and homogeneous mixing of the active compound with a liquid and/or finely divided solid carrier, after which the product, if necessary, is shaped. For example, a tablet can thus be prepared by pressing or shaping a powder or granules of the compound, if appropriate with one or more additional constituents. Pressed tablets can be produced by tableting the compound in free-flowing form, such as, for example, a powder or granules, if appropriate mixed with a binder, lubricant, inert diluent and/or a (number of) surface-active/dispersing agent(s) in a suitable machine. Shaped tablets can be produced by shaping the pulverulent compound moistened with an inert liquid diluent in a suitable machine.

Pharmaceutical compositions suitable for peroral (sublingual) administration include lozenges, which contain a compound of the formula (I) with a flavoring, customarily sucrose and gum arabic or tragacanth; and pastilles, which include the compound in an inert base such as gelatin and glycerol or sucrose and gum arabic.

Other suitable active compounds for the combination preparations include, but are not limited to:

all antidiabetics mentioned in Rote Liste 2001, Chapter 12. They can be combined with the compounds of the formula I according to the invention to achieve a synergistically enhanced action. The active compound combination can be administered either by separate administration of the active compounds to the patient or in the form of combination preparations comprising a plurality of active compounds in a single pharmaceutical preparation.

Antidiabetics include insulin and insulin derivatives, such as, for example, Lantuso® or HMR 1964, GLP-1 derivatives, such as, for example, those disclosed by Novo Nordisk A/S in WO 98/08871, and oral hypoglycemic active compounds.

Examples of oral hypoglycemic active compounds include sulfonylureas, biguadines, meglitinides, oxadiazolidinediones, thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1 agonists, potassium channel openers, such as, for example, those disclosed by Novo Nordisk A/S in WO 97/26265 and WO 99/03861, insulin sensitizers, inhibitors of liver enzymes involved in stimulating gluconeogenesis and/or glycogenolysis, modulators of glucose uptake, compounds which modulate lipid metabolism, such as antihyperlipidemic active compounds and antilipidemic active compounds, compounds that reduce food intake, PPAR and PXR agonists and active compounds that act on the ATP-dependent potassium channel of the beta cells.

In one embodiment of the invention, the compounds of the formula I are administered in combination with an HMGCoA reductase inhibitor such as simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, cerivastatin, or rosuvastatin.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a cholesterol absorption inhibitor, such as, for example, ezetimibe, tiqueside, or pamaqueside.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR gamma agonist, such as, for example, rosiglitazone, pioglitazone, JTT-501, GI 262570.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a PPAR alpha agonist, such as, for example, GW 9578, or GW 7647.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a mixed PPAR alpha/gamma agonist, such as, for example, GW 1536, AVE 8042, AVE 8134, or AVE 0847.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a fibrate, such as, for example, fenofibrate, clofibrate, or bezafibrate.

In another embodiment of the invention, the compounds of the formula I are administered in combination with an MTP inhibitor, such as, for example, Bay 13-9952, BMS-201038, or R-103757.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a bile acid absorption inhibitor, such as, for example, HMR 1453.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a CETP inhibitor, such as, for example, Bay 194789.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a polymeric bile acid adsorber, such as, for example, cholestyramine, or colesolvam.

In another embodiment of the invention, the compounds of the formula I are administered in combination with an LDL receptor.inducer, such as, for example, HMR1171, or HMR1586.

In another embodiment of the invention, the compounds of the formula I are administered in combination with an ACAT inhibitor, such as, for example, avasimibe.

In another embodiment of the invention, the compounds of the formula I are administered in combination with an antioxidant, such as, for example, OPC-14117.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein lipase inhibitor, such as, for example, NO-1886.

In another embodiment of the invention, the compounds of the formula I are administered in combination with an ATP citrate lyase inhibitor, such as, for example, SB-204990.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a squalene synthetase inhibitor, such as, for example, BMS-188494.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a lipoprotein(a) antagonist, such as, for example, Cl-1027 or nicotinic acid.

In another embodiment of the invention, the compounds of the formula I are administered in combination with a lipase inhibitor, such as, for example, Orlistat.

In another embodiment of the invention, the compounds of the formula I are administered in combination with insulin.

In another embodiment, the compounds of the formula I are administered in combination with a sulfonylurea, such as, for example, tolbutamide, glibenclamide, glipizide or gliclazide.

In another embodiment, the compounds of the formula I are administered in combination with a biguanide, such as, for example, metformin.

In another embodiment, the compounds of the formula I are administered in combination with a meglitinide, such as, for example, repaglinide.

In another embodiment, the compounds of the formula I are administered in combination with a thiazolidinedione, such as, for example, troglitazone, ciglitazone, pioglitazone, rosiglitazone, or the compounds disclosed by Dr. Reddy's Research Foundation in WO 97/41097, for example 5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]phenyl]methyl]-2,4-thiazolidinedione.

In another embodiment, the compounds of the formula I are administered in combination with an α-glucosidase inhibitor, such as, for example, miglitol or acarbose.

In another embodiment, the compounds of the formula I are administered in combination with an active compound that acts on the ATP-dependent potassium channel of beta cells, such as, for example, tolbutamide, glibenclamide, glipizide, gliazide or repaglinide.

In another embodiment, the compounds of the formula I are administered in combination with more than one of the abovementioned compounds, for example in combination with a sulfonylurea and mefformin, a sulfonylurea and acarbose, repaglinide and metformin, insulin and a sulfonylurea, insulin and mefformin, insulin and troglitazon, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administered in combination with CART agonists, NPY agonists, MC3 and MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3-agonists, MCH (melanine-concentrating hormone) antagonists, CCK agonists, serotonin reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormone, growth hormone-releasing compounds, TRH agonists, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators or TR-β agonists.

In one embodiment of the invention, the further active compound is leptin.

In another embodiment, the further active compound is dexamphetamine or amphetamine.

In another embodiment, the further active compound is fenfluramine or dexfenfluramine.

In another embodiment, the further active compound is sibutramine.

In another embodiment, the further active compound is Orlistat.

In another embodiment, the further active compound is mazindol or phentermine.

In another embodiment, the compounds of the formula I are administered in combination with fiber, for instance insoluble fiber, such as, for example, Caromax®.

The combination with Caromax® can be administered in a single preparation or by separate administration of compounds of the formula I and Caromax®. Here, Caromax® can also be administered in the form of food, such as, for example, in bakery goods or muesli bars. Compared to the individual active compounds, the combination of compounds of the formula I with Caromax® is, in addition to providing an enhanced action, also characterized by its improved tolerability, for example with respect to the lowering of LDL cholesterol.

It goes without saying that each suitable combination of the compounds according to the invention with one or more of the compounds mentioned above and optionally one or more further pharmacologically active substances is included in the scope of the present invention.

The scope of the invention also includes both, stereoisomer mixtures of compounds of the formula I and the pure stereoisomers of the formula I, as well as diastereomer mixtures of the compounds of formula I and the pure diastereomers. The mixtures may, for example, be separated by known chromatographic means.

One embodiment of the invention includes both racemic and enantiomerically pure compounds of the formula I of the following structure:

Examples of amino protective groups that can be used include the benzyloxycarbonyl (Z) radical, which can be removed by catalytic hydrogenation; the 2-(3,5-dimethyloxyphenyl)propyl(2)oxycarbonyl(Ddz) or trityl (Trt) radical, which can be removed by weak acids; the t-butylcarbamate (BOC) radical, which can be removed by 3M hydrochloric acid; and the 9-fluorenylmethyloxycarbonyl (Fmoc) radical, which can be removed using secondary amines.

Another embodiment of the invention relates to a process for preparing diphenylazetidinone derivatives of formula I.

Y can be S, O, (C═O), (C═S), CH═CH, C≡C, N((C₁-C₆)-alkyl), N(phenyl), N((C₁-C₆)-alkyl-phenyl), N(CO—(CH₂)₁₋₁₀—COOH) or NH;

R11 can be H or, if Y=(C═O) or (C═S), then R11 can be OH;

W, Y′ and W′ can, independently of one another and of Y, be —S(O)_(m)— (where m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl), —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— or —NH— or a bond;

x, y and z independently of one another can be 0 to 10.

In compound II, —(CH₂)x-Y—R11 can alternatively also be attached to one of the other two phenyl rings.

The process for preparing compounds of the formula I comprises reacting, for example, an amine or a hydroxy compound of the formula II with an alkylating or acylating agent whichmay carry a further functionality(for example in the omega position), if appropriate in protected form. This functionality may be used (after deprotection) for attaching (LAG), for example with the formation of ether, amine or amide bonds.

The examples below serve to illustrate the invention in more detail, without limiting the invention to the products and embodiments described in the examples.

EXAMPLE I 4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6)

a) 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]4-phenyl-oxazolidin-2-one (1)

27 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one, 13.6 g of tert-butyldimethylsilyl chloride and 10.2 g of imidazole were dissolved in 36 ml of dimethylformamide and stirred at 60° C. for 90 min. After the reaction ended, the mixture was dissolved in ethyl acetate and extracted two times with water. The organic phase was dried over magnesium sulfate, filtered and concentrated under reduced pressure. This produced 3-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one (1) of molecular weight 471.65 (C₂₆H₃₄FNO₄Si); MS (ESI): 340.28 (MH⁺—HOSi(CH₃)₂C(CH₃)₃).

b) 4-[5-(tert-butyidimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2)

16.2 g of 3-[5-(tert-butyidimethylsilanyloxy)-5-(4-fluorophenyl)-pentanoyl]-4-phenyloxazolidin-2-one were dissolved in 350 ml of dichloromethane. 19.8 ml of Hünig base and 10.14 g of 4-[(4-methoxyphenylimino)methyl]benzonitrile were added, and the solution was cooled to −10° C. 8.52 ml of trimethylsilyl triflate were added to the cooled solution, and the mixture was stirred at −10° C. for 30 min. The solution was then cooled to −30° C., and 44 ml of titanium tetrachloride solution were added. The reaction mixture was stirred at a temperature ranging from −30 to −40° C. for 2 h. The solution was then allowed to warm to room temperature and the reaction solution was washed successively with 200 ml of 2N sulfuric acid, 300 ml of 20% strength sodium hydrogen sulfite solution and sat. sodium chloride solution. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure.The residue was purified on silica gel using n-heptane/ethyl acetate 3/1. This produced 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2) of molecular weight 707.93 (C₄₁H₄₆FN₃O₅Si); MS (ESI): 590.51 (MH⁺—C₇H₅N₂).

c) 4-[3-[3-(tert-butyidimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzonitrile (3)

13.2 g of 4-[5-(tert-butyldimethylsilanyloxy)-5-(4-fluorophenyl)-1-(4-methoxyphenyl)-2-(2-oxo4-phenyloxazolidine-3-carbonyl)pentylamino]benzonitrile (2) were dissolved in 380 ml of methyl tert-butylether. 18.6 ml of N,O-bis(trimethylsilyl)acetamide and 1.86 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. After the reaction ended, 10 ml of acetic acid were added, the reaction mixture was concentrated under reduced pressure and the residue was purified on silica gel using toluene/ethyl acetate 50/1. This produced 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (3) of molecular weight 544.75 (C₃₂H₃₇FN₂O₃Si); MS (ESI): 545.56 (M+H⁺).

d) 4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4)

3.5 g of 4-[3-[3-(tert-butyldimethylsilanyloxy)-3-(4-fluorophenyl)propyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile were dissolved in 65 ml of tetrahydrofuran. 0.74 ml of acetic acid and 8.03 ml of a 1 M solution of tetrabutylammonium fluoride in tetrahydrofuran were added and the mixture was stirred at room temperature for 2 h. Another 4.82 ml of the tetrabutylammonium fluoride solution were then added, and the mixture was stirred at reflux temperature for another 3 h. The cooled reaction mixture was concentrated under reduced pressure and the residue was purified by silica gel chromatography using n-heptane/ethyl acetate 2/1. This produced 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile (4) of molecular weight 430.48 (C₂₆H₂₃FN₂O₃); MS (ESI): 431.24 (M+H⁺).

e) 1-(4-Aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5)

1.22 g of 4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]-benzonitrile were dissolved in 90 ml of ethanol. 10 ml of conc. ammonia solution and an excess of Raney nickel were added, and the mixture was stirred at 60° C. and a hydrogen pressure of 10 bar for 8 h. Overnight, the reaction mixture cooled to room temperature, and the next day, the catalyst was removed, the filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography using dichloromethane/methanol/ammonia solution 10/1/0.1. This produced 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)-azetidin-2-one (5) of molecular weight 434.51 (C₂₆H₂₇FN₂O₃); MS. (ESI): 418.2 (MH⁺—NH₃).

4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxo-azetidin-1-yl]benzylamino}butane-1-sulfonic acid (6)

At room temperature, 87 mg of the above benzylamine were dissolved in 3 ml of dry acetonitrile, 40 μl of 1,4-butanesultone were added and the mixture was heated under reflux for 12 h. The cooled reaction solution was concentrated under reduced pressure and purified chromatographically (silica, gel; dichloromethane/methanol 85/15+10% water). This gives 4-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylamino}butane-1-sulfonic acid (6) of molecular weight 570.69 (C₃₀H₃₅FN₂O₆S); MS (ESI): 553.28 (MH⁺—H₂O).

EXAMPLE II 2-[(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butyl)methylamino]ethylsulfonic acid (8)

130 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 120 mg of N-methyltaurine in 2 ml of water and 60 mg of potassium carbonate were then added. The mixture was stirred at 50° C. for 24 h. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product (50 mg) as an oil.

C₃₂H₃₉FN₂O₇S ESIMS m/z: 614 (M⁺)

EXAMPLE III [2-(4-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butylamino)ethyl]phosphonic acid (9)

200 mg of 3-[3-(4-fluorophenyl)-3-hydroxypropyl]-1-[4-(4-fluorobutoxy)phenyl]-4-(4-methoxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 165 mg of 1-aminoethylphosphate and 247 mg of potassium carbonate dissolved in 3 ml of water were then added. The mixture was stirred at 90° C. for 8 h. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product (47 mg) as an oil.

C₃₁H₃₈FN₂O₇P ESIMS m/z: 600 (M⁺)

EXAMPLE IV Phosphoric acid mono{6-[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butylamino]hexyl}ester (10)

115 mg of 1-(4-fluorofluorophenyl)-3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-4-[4-(2-fluoromethoxyethoxy)phenyl]azetidin-2-one (7) were dissolved in 6 ml of absolute methanol. 130 mg of 6-amino-1-hexyl phosphate in 1.5 ml of water and 107 mg of potassium carbonate were then added. The mixture was stirred at 70° C. overnight. The reaction mixture was concentrated using a rotary evaporator and the residue was purified by preparative chromatography. Freeze-drying gave the product as an oil.

C₃₄H₄₃F₂N₂O₇P ESIMS m/z: 660 (M⁺)

EXAMPLE V 4-{4-[3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]phenoxy}butane-1-sulfonic acid (12)

160 mg of 3-[3-(4-fluorofluorophenyl)-3-hydroxypropyl]-1-(4-hydroxyphenyl)-4-(4-methoxyphenyl)azetidin-2-one (11) were dissolved in 4 ml of absolute dimethylformamide. 210 mg of powdered potassium carbonate and 42 mg of 1,4,-butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was concentrated under oil pump vacuum, taken up in dichloromethane and washed 1× with water. The aqueous phase was acidified with 2N hydrochloric acid and extracted 2× with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated. The residue was chromatographed on a 10 g SiO₂ cartridge (dichloromethane/methanol=5/1). The product (72 mg) was obtained as an oil.

C₂₉H₃₂FNO₇S ESIMS m/z: 557 (M⁺)

EXAMPLE VI 4-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butane-1-sulfonic acid (13)

250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg of powdered potassium carbonate and 69 μl of 1,4, -butanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was chromatographed on a 10 g SiO₂ cartridge (dichloromethane/methanol=5/1) and crystallized from diethyl ether. The product (131 mg) was obtained as a solid.

C₂₈H₂₉F₂NO₆S ESIMS m/z: 546 (M⁺)

EXAMPLE VII 3-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-oxoazetidin-2-yl}phenoxy)propan-1-sulfonin acid (14)

250 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one (7) were dissolved in 6 ml of absolute dimethylformamide. 337 mg of powdered potassium carbonate and 59 μl of 1,3,-propanesultone were added. The mixture was stirred at room temperature overnight. The reaction solution was filtered and concentrated under oil pump vacuum. The residue was chromatographed on a 10 g SiO₂ cartridge (dichloromethane/methanol=5/1) and crystallized from diethyl ether. The product (250 mg) was obtained as a solid.

C₂₇H₂₇F₂NO₆S ESIMS m/z: 532 (M⁺)

EXAMPLE VIII (4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzylcarbamoyl)methanesulfonic acid (18)

a) 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyloxazolidine-3-carbonyl)-pentyl]-benzonitrile (15)

Under argon, 2.5 g of 3-[5-(4-fluorophenyl)-5-hydroxypentanoyl]-4-phenyloxazolidin-2-one were dissolved in 30 ml of dichloromethane. 3.9 g of 4-[(4-fluorophenylimino)-methyl]-benzonitrile were added and the mixture was cooled to −10° C. 6.4 ml of diisopropylethylamine and, over a period of 30 min, 4.05 ml of trimethylsilyl chloride were added to this mixture so that the temperature did not exceed −5° C. The mixture was stirred at this temperature for 1 additional hour and then cooled to −25° C. 0.8 ml of titanium tetrachloride were then added slowly. The dark mixture was stirred at a temperature ranging from −25 to −30° C. overnight and then decomposed using 35 ml of a 7 percent strength solution of tartaric acid and then stirred at room temperature for another hour. 15 ml of a 20 percent strength solution of sodium bicarbonate were then added, and the mixture was again stirred for 1 hour. Following magnesium sulfate and concentrated to about 10 ml. Following the addition of 2 ml of bistrimethylsilylacetamide, the mixture was heated at reflux for 30 min and then concentrated under reduced pressure. The residue was crystallized using ethyl acetate/heptane. The product was filtered off with suction and dried under reduced pressure. This gave the product of molecular weight 653.81 (C₃₇H₃₇F₂N₃O₄Si); MS (ESI+): 654.3 (M+H⁺), 582.2 (M+H⁺—Si(CH₃)₃).

b) {1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16)

2 g of 4-[5-(4-Fluorophenyl)-1-(4-fluorophenylamino)-5-hydroxy-2-(2-oxo-4-phenyl-oxazolidine-3-carbonyl)-pentyl]-benzonitrile (15) were dissolved in 20 ml of methyl-tert-butyl ether and, together with 100 mg of tetrabutylammonium fluoride trihydrate and 1.3 ml of bistrimethylsilyl acetamide, heated at 40° C. for about 1 h. The reaction was monitored by thin-layer chromatography. After the reaction ended, 0.2 ml of glacial acetic acid was initially added and the mixture was stirred for 30 min and then concentrated. 20 ml of a mixture of isopropanol/2N sulfuric acid=10:1 were added to the residue, and the mixture was stirred for 1 hour. Following addition of a spatula tip of solid sodium bicarbonate, the mixture was again concentrated under reduced pressure, the residue was taken up in ethyl acetate and the organic phase was washed with water and dried. The residue was, after removal of the solvent, purified by column chromatography (SiO₂, CH₂Cl₂/methanol=100:1). This gave the product of molecular weight 418.45 (C₂₅H₂₀F₂N₂O₂); MS (DCI+): 419 (M+H⁺).

c) 4-(4-Aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one (17)

200 mg of {1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzonitrile (16) were dissolved in 20 ml of ethanol and, with 0.5 ml of conc. ammonia, hydrogenated over Raney nickel at a hydrogen pressure of 75 bar and at 25° C. for 30 hours. The catalyst was filtered off with suction, the mixture was concentrated under reduced pressure and the residue was purified by column filtration (SiO₂, CH₂Cl₂/methanol/conc. NH₃=100:10:1). This gave the product of molecular weight 422.5 (C₂₅H₂₂F₂N₂O₂); MS (DCI+): 423 (M+H⁺), 405 (M+H⁺-H₂O).

d) (4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}-benzylcarbamoyl)methanesulfonic acid (18)

A solution of 120 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (17), and 48 μl of diisopropylethylamine in 1 ml of dimethylformamide was added to a solution of 40 mg of sulfoacetic acid, 110 μl of diisopropylcarbodiimide, and 76 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 544.58 (C₂₇H₂₆F₂N₂O₆S₁); MS (ESI) 527.10 (M+H⁺—H₂O)

EXAMPLE IX {4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methanesulfonic acid (19)

A solution of 60 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one (5) in 1 ml of dimethylformamide was added to a solution of 20 mg of sulfoacetic acid, 55 μl of diisopropylcarbodiimide, 38 mg of hydroxybenzotriazole in 1 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 556.61 (C₂₈H₂₉F₁N₂O₇S₁); MS (ESI) 539.05 (M+H⁺—H₂O)

EXAMPLE X N-(4-{1-(4-Fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}benzyl)succinaminic acid (20)

A solution of 100 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]azetidin-2-one (17), and 33 μl of triethylamine in 2 ml of dimethylformamide was added to a solution of 279 mg of succinic acid, 92 μl of diisopropylcarbodiimide, 80 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 522.55 (C₂₇H₂₆F₂N₂O₆S₁); MS (ESI) 545.19 (M+Na⁺)

EXAMPLE XI {2-[2-({4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}methoxy)ethoxy]ethoxy}acetic acid (21)

A solution of 64 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]4-(4-methoxyphenyl)azetidin-2-one (5), and 21 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 327 mg of 3,6,9-trioxaundecanedioic acid, 57 μl of diisopropylcarbodiimide, 50 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 638.70 (C₃₄H₃₉F₁N₂O₉); MS (ESI) 639.27 (M+H⁺)

EXAMPLE XII 4-((3-Carboxypropionyl)-{4-[3-[3-(4-fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzyl}amino)-4-oxobutyric acid (22)

A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 23 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 190 mg of succinic acid, 63 μl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC (Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 634.4 (C₃₄H₃₅F₁N₂O₉); MS (ESI-neg.) 633.22 (M−H⁺)

EXAMPLE XIII 11-{4-[3-[3-(4-Fluorophenyl)-3-hydroxypropyl]-2-(4-methoxyphenyl)-4-oxoazetidin-1-yl]benzylcarbamoyl}undecanoic acid (23)

A solution of 70 mg of 1-(4-aminomethylphenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-methoxyphenyl)azetidin-2-one (5), and 23 μl of triethylamine in 1 ml of dimethylformamide was added to a solution of 371 mg of dodecanedioic acid, 63 μl of diisopropylcarbodiimide, 55 mg of hydroxybenzotriazole in 2 ml of dimethylformamide, and the mixture was stirred at room temperature for 12 h. The reaction solution was concentrated and separated by HPLC(Knauer Eurospher-100-10-C18, water (0.1% trifluoroacetic acid)/acetonitrile (0.1% trifluoroacetic acid)=80/20→10/90). This gave the product of molecular weight 646.81 (C₃₈H₄₇F₁N₂O₆); MS (ESI) 647.35 (M+H⁺)

TABLE 1 Compounds of the formula I I

Molecular weight of the free base Molecular or acid weight Ex. R1, R2 R3, R4 R5, R6 (calculated) (found) XIV

para-F, H para-F, H 531.58 532.4(MH⁺) XV

para-F, H para-F, H 502.54 503.3(MH⁺) XVI para-F, H

para-F, H 514.58 515.4(MH⁺) XVII para-O—CH₃, H

para-F, H 599.68 599.21(M⁺) XVIII para-O—CH₃, H

para-F, H 739.95 740.42(MH⁺) XIX para-O—CH₃, H

para-F, H 599.60 600.34(MH⁺) XX para-O—CH₃, H

para-F, H 534.59 534.4(MH⁺) XXI

para-F, H para-F, H 578.66 561.25(MH⁺—H₂O) XXII

para-F, H para-F, H 634.77 617.31(MH⁺—H₂O) XXIII para-F, H

para-F, H 585.65 567.70(MH⁺—H₂O) XXIV para-O—CH₃, H

para-F, H 557.64 557.19(M⁺) XXV

Para-F, H para-F, H 660.70 660.28(M⁺) XXVI para-O—CH₃, H

para-F, H 600.62 600.24(M⁺) XXVII para-O—CH₃, H

para-F, H 614.73 597.32(M—H₂O)⁺¹ XXVIII

para-F, H para-F, H 559,64 560,4(MH⁺) XXIX

para-F, H para-F, H 545,61 546,3(MH⁺) XXX

para-F, H para-F, H 727,91 710.23(MH⁺—H₂O) XXXI para-O—CH₃, H

para-F, H 753,93 752,32(M—H⁺);gemessenim Negativ-modus) XXXII

para-F, H para-F, H 573.62 572,09(M—H+);gemessenim Negativ-modus) XXXIII

para-F, H para-F, H 587,67 586,18(M—H+);gemessenim Negativ-modus)

Using the method described below, the activity of the compounds of the formula I according to the invention was examined:

Effect of the compounds of the invention on cholesterol absorption and 3H-taurocholic acid excretion using fecal excrement of mice, rats or hamsters

NMRI mice, Wistar rats, or Golden Syrian hamsters (in groups of n=4-6) were kept in metabolic cages, where they were fed with a standard diet (Altromin, Lage (Lippe)). The afternoon prior to the administration of the radioactive tracers (14C-cholesterol), the feed was removed and the animals were adapted to grates.

Additionally, the animals were labeled s.c. with 3H-TCA (taurocholic acid) (for example 1 μCi/mouse up to 5 μCi/rat) 24 hours prior to the peroral administration of the test meal (14C-cholesterol in Intralipid® 20, Pharmacia-Upjohn).

Cholesterol absorption test: 0.25 ml/mouse Intralipid®D 20 (Pharmacia-Upjohn) ((spiked with 0.25 μCi of 14C-cholesterol in 0.1 mg of cholesterol) was administered perorally by gavage.

Test substances were prepared separately in 0.5% methylcellulose (Sigma)/5% Solutol (BASF, Ludwigshafen) or a suitable vehicle.

The administration volume of the test substance was 0.5 ml/mouse. The test substance was administered immediately prior to the test meal (Intralipid labeled with 14C-cholesterol) (cholesterol absorption test).

The feces were collected over a period of 24 h. Fecal elimination of 14C-cholesterol and 3H-taurocholic acid (TCA) was determined after 24 hours.

The livers were removed and homogenized, and aliquots were incinerated in an oximate (Model 307, Packard) to determine the amount of 14C-cholesterol that had been taken up/absorbed.

Evaluation

Feces Samples

The total weight was determined, the sample was made up with water to a defined volume and then homogenized, and an aliquot was evaporated to dryness and incinerated in an oximate (Model 307 from Packard for the incineration of radioactively labeled samples). The amount of radioactive 3H—H₂O and 14C—CO₂ was extrapolated to the amount of 3H-taurocholic acid and 14C-cholesterol, respectively, that was excreted (dual isotope technique). The ED₂₀₀ values were interpolated from a dose-effect curve as those doses at which the excretion of TCA or cholesterol was doubled, based on a control group treated at the same time.

Liver Samples

The amount of-14C-cholesterol taken up by the liver was based on the administered dose. The ED50 values were interpolated from a dose-effect curve as the dose at which the uptake of 14C-cholesterol by the liver was halved (50%), based on a control group.

The ED50 values below demonstrate the activity of the compounds of the formula I according to the invention

Example No. ED₅₀ (liver) [mg/mouse] I 1.0 II >0.1 IV 0.3 VIII 0.3 IX <1.0 X <1.0 XIII <0.1 XVIII 0.005 XXI 0.1 XXII 0.1 XXV 0.3 XXVIII 0.3

As can be seen from the table, the compounds of the formula I have very good cholesterol-lowering action.

Bioabsorption

The bioabsorption of the compounds of the formula I was examined using the Caco cell model (A. R. Hilgers et al., Caco-2 cell monolayers as a model for drug transport across the intestinal mucosa, Pharm. Res. 1990, 7, 902).

From the measured data, it can be seen that the bioabsorption of the compounds of the formula I according to the invention was considerably lower than that of the compounds described in the prior art (reference structure): 

1. A compound of the formula I,

wherein R1, R2, R3, R4, R5, and R6, independently of one another, are chosen from: LAG; (C₁-C₃₀)-alkyl, wherein the (C₁-C₃₀)-alkyl is substituted by q LAG units; (C₁-C₃₀)-alkyl, wherein the (C₁-C₃₀)-alkyl is substituted by q LAG units; and wherein at least one carbon atom of the alkyl radical is replaced by a radical chosen from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl), —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—-COOH)— and —NH—; H, F, CI, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; wherein (LAG) is —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀—O—P(O)(OH)₂, or —(CH₂)₀₋₁₀—COOH and wherein q is 1-5; and wherein at least one of the radicals R1 to R6 must have the meaning: LAG; or (C₁-C₃₀)-alkyl, wherein the (C₁-C₃₀)-alkyl is substituted by q LAG units; or (C₁-C₃₀)-alkyl, wherein the (C₁-C₃₀)-alkyl is substituted by q LAG units; and wherein at least one carbon atom of the alkyl radical is replaced by a radical chosen from: —S(O)_(m)— (wherein m=0-2), —O—, —(C═O)—, —(C═S)—, —CH═CH—, —C≡C—, —N((C₁-C₆)-alkyl)-, —N(phenyl)-, —N((C₁-C₆)-alkyl-phenyl)-, —N(CO—(CH₂)₁₋₁₀—COOH)— and —NH—, or a pharmaceutically acceptable salt thereof, in any stereoisomeric form, or a mixture of any such compounds in any ratio; with the proviso that the compound is not 2-{[4-(4-{1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-oxoazetidin-2-yl}phenoxy)butyl]methylamino}ethanesulfonic acid, or a compound wherein the radicals R1-R6 have the meaning —O—(CH₂)₁₋₁₀—COOH, (C₁-C₆)-alkylene-COOH or —COOH.
 2. A compound as claimed in claim 1, wherein R2, R4, R5, and R6, independently of one another, are chosen from: H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R1 and R3, independently of one another, are chosen from: LAG; (C₁-C₃₀)-alkylene-(LAG); (C₁-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of the alkylene radical is replaced by —O—, —(C═O)—, —N(CH₃)— or —NH—; H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6 and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; wherein (LAG) is —(CH₂)₀₋₁₀—SO₃H; —(CH₂)₀₋₁₀—P(O)(OH)₂, —(CH₂)₀₋₁₀—O—P(O)(OH)₂, or —(CH₂)₀₋₁₀—COOH; wherein at least one of the radicals R1 or R3 must have the meaning: LAG; or (C₁-C₃₀)-alkylene-(LAG); or (C₁-C₃₀)-alkylene-(LAG), wherein at least one carbon atom of the alkylene radical is replaced by —O—, —(C═O)—, —N(CH₃)—or —NH—.
 3. A compound as claimed in claim 1, wherein R2, R4, R5, and R6, independently of one another, are chosen from: H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂—(CH₂)_(n)-phenyl, wherein n=0-6 and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; R1 and R3, independently of one another, are chosen from: —(CH₂)₀₋₁—Y—W—Y′—W′-(LAG); —(CH₂)₀₋₁—Y—W—(C_(1—)C₂₅)-alkylene-Y′—W′-(LAG); —(CH₂)₀₋₁—Y—W—(C_(1—)C₂₅)-alkylene-Y′—W′-(LAG), wherein at least one carbon atom of the alkylene radical is replaced by —O—; H, F, Cl, Br, I, CF₃, NO₂, N₃, CN, COO(C₁-C₆)-alkyl, CONH₂, CONH(C₁-C₆)-alkyl, CON[(C₁-C₆)-alkyl]₂, (C₁-C₆)-alkyl, (C₂-C₆)-alkenyl,(C₂-C₆)-alkynyl, or O—(C₁-C₆)-alkyl, wherein the alkyl radical is unsubstituted or at least one hydrogen in the alkyl radical is replaced by fluorine; C(═NH)(NH₂), PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-phenyl, SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-phenyl, SO₂—(C₁-C₆)-alkyl, or SO₂-(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl radical is unsubstituted or substituted one or two times, each substituent chosen independently from: F, Cl, Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, and NH₂; and NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NHCO(C₁-C₆)-alkyl, phenyl, or O—(CH₂)_(n)-phenyl, wherein n=0-6, and wherein the phenyl ring is unsubstituted or substituted one, two, or three times, each substituent chosen independently from: F, Cl, Br, I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl, and CONH₂; wherein Y, W, Y′ W′, independently of one another, are chosen from: NH, NCH₃, C═O, O, a bond, and S(O)_(m), wherein m=0-2; or Y—W together represent a bond; or Y′—W′ together represent a bond; and wherein (LAG) is chosen from: —(CH₂)₀₋₁₀—SO₃H, —(CH₂)₀₋₁₀—P(O)(OH)₂, (CH₂)₀₋₁₀—O—P(O)(OH)₂, and —(CH₂)₀₋₁₀—COOH; and wherein at least one of the radicals R1 or R3 must have the meaning: —(CH₂)₀₋₁—Y—W—Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C_(1—)C₂₅)-alkylene-Y′—W′-(LAG); or —(CH₂)₀₋₁—Y—W—(C_(1—)C₂₅)-alkylene-Y′—W′-(LAG); wherein at least one carbon atom of the alkylene radical is replaced by —O—.
 4. A compound as claimed in claim 1, wherein (LAG) is —(CH₂)₀₋₁₀—COOH or —(CH₂)₀₋₁₀—SO₃H.
 5. A pharmaceutical composition, comprising an effective amount of at least one compound as claimed in claim
 1. 6. A pharmaceutical composition, comprising an effective amount of at least one compound as claimed in claim 1, and at least one additional active compound.
 7. The pharmaceutical composition of claim 6, wherein the at least one additional active compound is chosen from compounds that normalize lipid metabolism.
 8. The pharmaceutical composition of claim 6, wherein the at least one additional active compound is chosen from antidiabetics, hypoglycemically active compounds, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbers, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, biguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active compounds which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, MC4 agonists, orexin agonists, H3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β33 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin-reuptake inhibitors, mixed serotonin and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, decoupling protein 2 or 3 modulators, leptin agonists, DA agonists,lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β-agonists and amphetamines.
 9. A process for preparing a pharmaceutical composition comprising at least one compound as claimed in claim 1, comprising mixing the at least one compound with a pharmaceutically acceptable carrier and bringing this mixture into a form suitable for administration.
 10. A method for treating hyperlipidemia, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in claim
 1. 11. A method for lowering the serum cholesterol concentration, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in claim
 1. 12. A method for treating arteriosclerotic manifestations, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in claim
 1. 13. A method for treating a patient afflicted with insulin resistance, comprising administering to a patient in need thereof an effective amount of at least one compound as claimed in claim
 1. 14. The pharmaceutical composition of claim 8, wherein the at least one additional active compound is chosen from bromocriptine and 4, 7, 10, 13, 16, 19-docosahexaenoic acid dopamine conjugate. 